This proposal describes a five-year research and training plan that will facilitate the transition of Dr. Jennifer Alexander-Brett, MD PhD to an independent academic researcher. She has a strong background in basic science research and medicine and has completed post-graduate training in Internal Medicine and Pulmonary/Critical Care Medicine. The primary goal of this proposal is to provide the framework and support necessary for Dr. Alexander-Brett to fulfill her career goals as a physician-scientist through transition to independent scientific investigation in pulmonary disease. This work will be carried out at Washington University School of Medicine under the supervision of Dr. Michael J. Holtzman. Washington University is well known for its strong history of research. Likewise, Dr. Holtzman is an international leader in lung biology with a focus on mechanisms of chronic obstructive lung diseases such as COPD and asthma and a highly successful track record of mentoring. An advisory committee with diverse expertise will provide career guidance and scientific feedback. A detailed career development plan is proposed that will include regular participation in scholarly activities, scientific presentations, and a timeline for preparation of manuscripts for publication and an eventual R01 application in a pathway to independence. The proposed research plan will focus on mechanistic studies of chronic airway disease with the long-term goal of defining pathways amenable to therapeutic intervention. The initial training phase of this work takes advantage of a parainfluenza virus-induced mouse model of chronic airway disease that was developed and validated in the mentor's lab, while later stages are designed to develop the candidate's independent research in structural biology. Specifically, this proposal will address the function of epithelial- derived cytokine IL-33 as a driver of innate immune activation and consequent mucus overproduction. Initial work on this project has demonstrated that chronic airway disease depends on an IL-33-IL-33R signal in the mouse model, and this signal is also activated in humans with comparable disease due to COPD. However, the molecular mechanism of epithelial IL-33 function in airway disease remains largely undefined and will therefore be approached with three Specific Aims: Aim 1 will address the cellular sources and effectors of IL-33 activity in the mouse model. Aim 2 will focus on the functional characterization of IL-33-expressing epithelial cells as a progenitor population that potentially skews airway differentiation toward mucus overproduction. Aim 3 targets the cellular and eventually structural biology of IL-33 activation and release in epithelial cells. Together, these aims will address key steps in the pathologic sequence of epithelial-innate immune interactions that drive chronic airway disease, and allow Dr. Alexander-Brett to develop a high- level research career focused on regulating a key cytokine system in inflammatory lung disease.